BioWorld International Correspondent

LONDON - The discovery of a protein that plays a role in the development of allergic response in the eye could lead to new treatments for allergies that affect the eye, such as hay fever, as well as asthma and eczema.

The protein, called MIP-1a, helps trigger the release of the chemicals that cause signs and symptoms of allergy, such as redness, itching and inflammation. Drugs that block the action of MIP-1a already are available, and the researchers who carried out the study now are evaluating whether those, and similar compounds, can help treat allergic diseases.

Santa Jeremy Ono, GlaxoSmithKline professor of biomedical sciences at University College London and Moorfields Eye Hospital in London, said: "Clinical trials are anticipated shortly and if they prove effective, these studies may lead to new therapies within the next five to seven years."

He told BioWorld International that unpublished studies suggest blocking MIP-1a can similarly inhibit allergic reactions in other tissues, giving "reason for optimism."

Ono and colleagues reported their study in a paper titled "Macrophage inflammatory protein-1a as a co-stimulatory signal for mast cell-mediated immediate hypersensitivity reactions" in the Jan. 13, 2004, issue of Journal of Clinical Investigation.

The group has been trying to understand the molecular basis of the allergic response, with a view to developing better and safer treatments. Allergies affect more than a third of people in developed countries, with an estimated 17 million people in the UK who suffer from asthma, conjunctivitis, eczema or hay fever.

Allergic responses develop in two phases. The first involves an immediate hypersensitivity reaction within one hour of exposure to an allergen. As a result, cells of the immune system called mast cells - which play a role in the allergic reaction - release histamine and other molecules. That process is called degranulation. The molecules released include chemokines - proteins that help to mobilize white blood cells toward sites of inflammation. MIP-1a is among them.

The second phase, which occurs 12 to 24 hours after exposure, involves the recruitment of inflammatory cells to the site of inflammation.

Ono's group set out to examine the role of chemokines, including MIP-1a, in the first phase of the allergic response. Their studies showed that, in a mouse model of allergic conjunctivitis, the gene encoding MIP-1a began to be transcribed within 30 minutes of exposure to the allergen.

The cells producing MIP-1a (immune system cells called mononuclear cells) were found in a part of the eyelid in which there is a high concentration of mast cells. That led the team to speculate that MIP-1a might bind to the chemokine receptor CCR1, which is found on the surface of mast cells.

For the next experiment, the group injected MIP-1a beneath the conjunctiva of mice. They found that MIP-1a activated mast cells, causing them to degranulate.

The team also took mice lacking a functional gene for MIP-1a and studied how their mast cells behaved after exposure to an allergen. The authors wrote: "The MIP-1a-deficient mice failed to show clinical symptoms of immediate hypersensitivity. Remarkably, MIP-1a-deficient mice were almost devoid of acute inflammation. . . Every symptom of clinical disease - conjunctival edema, lid edema, lid redness, tearing/discharge and squinting - was strongly inhibited."

Further experiments showed that in mice exposed to an allergen, treatment with a neutralizing antibody specific for MIP-1a could "significantly suppress" the immediate hypersensitivity reaction, and that the suppression was due to direct effects of MIP-1a on the mast cell. The team also confirmed their hypothesis that MIP-1a acts by binding to CCR1 on the surface of mast cells.

The Phase I trial will evaluate the action of a CCR1 antagonist - a molecule that blocks the interaction of MIP-1a with the CCR1 receptor - on ocular allergy in humans. CCR1 antagonists have been developed in the past because chemokine receptors are important in many disease processes, including binding of viruses to cells during infection. "We believe that the drug will stop the disease before it even starts," Ono said.

He concluded: "We know that different inflammatory processes will involve different chemokines, so it should be possible to create extremely specific drugs that work at very early stages of the process, to treat asthma, eye allergy or dermatitis. Our studies also suggest that blocking the CCR1 interaction with MIP-1a has a prolonged therapeutic effect, lasting several days, which is clearly a desirable feature for a new drug."

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